S100A8/A9 Drives Neuroinflammatory Priming and Protects against Anxiety-like Behavior after Sepsis.
S100A8/A9 Drives Neuroinflammatory Priming and Protects against Anxiety-like Behavior after Sepsis.
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DOI：
10.4049/jimmunol.1700834
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发表时间：
2018-05-01
期刊：
影响因子：
--
通讯作者：
Singer BH
中科院分区：
文献类型：
--
作者：
Denstaedt SJ;Spencer-Segal JL;Newstead MW;Laborc K;Zhao AP;Hjelmaas A;Zeng X;Akil H;Standiford TJ;Singer BH
脓毒症通常会导致急性和慢性脑功能障碍，从而大大增加与这种常见疾病相关的发病率。脓毒症动物模型中的慢性脑功能障碍与持续的神经炎症和多种细胞因子的表达有关。然而，我们之前发现，脓毒症后小胶质细胞主要上调损伤相关分子 S100A8/A9。在这里，我们发现死于脓毒症的患者大脑中 S100A8/A9 增加，并且 S100A8 在星形胶质细胞和骨髓细胞中表达。使用脓毒症存活小鼠模型，我们发现脓毒症后 S100A8/A9 在大脑中持续表达。 S100A9 的表达对于向大脑募集中性粒细胞、启动小胶质细胞和巨噬细胞中活性氧的产生以及 TNFα 的分泌是必需的。然而，尽管改善了这些慢性炎症指标，S100A9 缺乏也会导致败血症后 2 周焦虑样行为恶化。总而言之，这些结果表明，S100A8/A9 导致脓毒症幸存者小鼠神经炎症的多个方面，包括粒细胞募集和小胶质细胞活性氧的启动以及细胞因子的产生，并且这些过程可能对脓毒症幸存者的焦虑行为具有保护作用。
Sepsis commonly results in both acute and chronic brain dysfunction, which dramatically increase the morbidity associated with this common disease. Chronic brain dysfunction in animal models of sepsis survival is linked to persistent neuroinflammation and expression of multiple cytokines. We have previously found, however, that microglia predominantly upregulate the damage associated molecule S100A8/A9 after sepsis. Here, we show that S100A8/A9 is increased in the brains of patients who died of sepsis, and that S100A8 is expressed in astrocytes and myeloid cells. Using a mouse model of sepsis survival, we show that S100A8/A9 is persistently expressed in the brain after sepsis. S100A9 expression is necessary for recruitment of neutrophils to the brain, and priming production of reactive oxygen species and TNFα secretion in microglia and macrophages. Despite improving these indices of chronic inflammation, however, S100A9 deficiency also results in worsened anxiety-like behavior 2 weeks after sepsis. Taken together, these results indicate that S100A8/A9 contributes to several facets of neuroinflammation in sepsis survivor mice, including granulocyte recruitment and priming of microglial reactive oxygen species and cytokine production, and that these processes may be protective against anxiety behavior in sepsis survivors.
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